Disitamab vedotin is a promising antibody-drug conjugate option undergoing evaluation for patients with metastatic urothelial cancer.
Arlene Siefker-Radtke, MD: Another interesting trial presented at this year’s ESMO [European Society for Medical Oncology] Congress is a trial in progress. It’s a trial looking at disitamab vedotin, which is another antibody-drug conjugate using that very toxic tubulin agent, monomethyl auristatin E. But in this case, the antibody targets HER2 expression. Why is HER2 expression important in patients with urothelial carcinoma? There have been data published showing that HER2-expressing urothelial tumors are often associated with higher grade, higher stage, and potentially adverse clinical outcomes. There’s an overall sense that the presence of HER2 on urothelial cancer tumor cells is associated with worse clinical outcomes. Perhaps being able to target this more directly could give us a means of enhancing the clinical activity of treatment in the poor prognostic patient cohort.
This antibody-drug conjugate—much like enfortumab vedotin [Padcev], which targets nectin-4 expression—brings monomethyl auristatin E more directly to HER2-overexpressing tumors. In early clinical trials that were presented at ASCO [American Society of Clinical Oncology Annual Meeting] a few years ago, we saw that this agent has clinical activity in patients with HER2-overexpressing tumors, with response rates that may be as high as 50% or more in HER2 2 or 3-plus patients. It even has clinical activity in HER2 1-plus–expressing tumors.
It brings to mind the question: how much targeting is enough? How much HER2 expression is enough to get uptake into the tumor cell? Why would this antibody-drug conjugate work in lower-expressing tumors? Is there a potential bystander effect? Perhaps you get enough drug into the low-expressing tumor cells and the tumor cells are killed, releasing drug in the circulation nearby that’s taken up in nearby cells or tumor cells that don’t have HER2 expression. Perhaps there’s some type of bystander effect by getting monomethyl auristatin E to the tumor microenvironment that enhances the uptake even in non–HER2-expressing cells.
A limitation of the previously presented data with disitamab vedotin is that it was in an exclusively Chinese patient population. We didn’t have a lot of data about central verification of objective response rate and how this therapy might perform in a more Caucasian patient population. Having ongoing trials of very promising agents that have shown clinical activity from our colleagues across the globe is very important in confirming that these data are reliable in our patients in the United States and other parts of the world. I look forward to seeing the outcomes of this clinical trial as it accrues patients using this novel method of bringing a very toxic tubulin agent directly to that HER2-expressing tumor.
Let’s consider how we make advances in the treatment of patients with bladder cancer in general. For decades, we’ve had systemic chemotherapy, but it took the development of a class of novel agents—immune checkpoint inhibitors—before we had additional agents approved for bladder cancer. The antibody-drug conjugates fit this paradigm extraordinarily well. I think of these as a new class of targeted agents that more directly target tumor cells. They bring these toxic chemotherapy agents directly to the tumor cell, resulting in an enhanced kill of that tumor cell and a reduction in adverse effects or toxicity.
We’ve seen several antibody-drug conjugates approved for bladder cancer, with enfortumab vedotin approved with level 1 evidence in the third-line setting. We’ve also seen very promising data with sacituzumab govitecan [Trodelvy], another antibody-drug conjugate targeting Trop-2–expressing tumors. It’s very clear that targeting tumors more directly can give us the opportunity to enhance the activity, enhance our ability to kill tumor cells, and reduce toxicity. This may also enhance the ability to give combination strategies and perhaps enhance the immune response against our patients’ urothelial tumors. I look forward to seeing additional antibody-drug conjugates developed. In this case, disitamab vedotin may be another promising way of targeting a poor prognostic HER2-expressing tumor.
Transcript edited for clarity.